Pyrazole derivatives

ABSTRACT

wherein ring A, RB2 and RB3 are as defined in claim 1, as well as the manufacture of such compounds and their subsequent use in the production of agrochemicals and/or pharmaceuticals.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No. 16/782,866, filed Feb. 5, 2020, which claims priority to Patent Application No. GB1901559.3 filed in the United Kingdom on Feb. 5, 2019, the entire contents of each which are incorporated herein by reference.

The present invention relates to pyrazole derivatives of formula (B) and formula (C) as described herein, which are valuable intermediates in the production of agrochemicals and pharmaceuticals. The invention extends to the manufacture of such pyrazole derivatives, and their subsequent use in the manufacture of agrochemicals and/or pharmaceuticals.

In a first aspect there is provided a compound of formula (B)

wherein ring A as is a di-substituted pyrazole, substituted a ring nitrogen by R^(B2) and substituted on a ring carbon by R^(B3), wherein R^(B2) is C₁-C₃ alkyl or C₁-C₃fluoroalkyl and R^(B3) is halogen, C₁-C₃fluoroalkyl, C₁-C₃haloalkoxy, C₁-C₃alkoxy, C₁-C₃haloalkyl, C₁-C₃fluoroalkyl, C₁-C₃haloalkoxy, C₁-C₃alkoxy, or C₁-C₃alkyl.

In a second aspect there is provided a compound of formula (C)

wherein ring A as is a di-substituted pyrazole, substituted on a ring nitrogen by R^(B2) and substituted on a ring carbon by R^(B3), wherein R^(B2) is C₁-C₃ alkyl or C₁-C₃fluoroalkyl, and R^(B3) is halogen, C₁-C₃fluoroalkyl, C₁-C₃haloalkoxy, C₁-C₃alkoxy, C₁-C₃haloalkyl, C₁-C₃fluoroalkyl, C₁-C₃haloalkoxy, C₁-C₃alkoxy, or C₁-C₃alkyl.

Compounds of formulae (B) and (C), may be used as intermediates in the manufacture of pharmaceuticals and agrochemicals comprising pyrazolo-pyrrolidone motifs. For example, US2007/0123508 describes 2-oxo-1-pyrrolidone derivatives for use as PAR2 inhibitors, compounds of formulae (B), (C), (D) and (E) may be used in the synthesis of such compounds wherein R¹ of the compound of US2007/0123508 is a substituted pyrazole. The manufacture of novel herbicidal compounds using compounds of formula formulae (B), and (C), is also described herein.

Compounds of formula (B) may be prepared from a halogenated pyrazole of formula (A)

wherein ring A, R^(B2) and R^(B3) are as defined above, and Hal is halogen selected from iodo, bromo and chloro, by reacting the compound of formula (A) with isopropylmagnesium chloride-lithium chloride in a suitable solvent, such as tetrahydrofuran, at −20° C. After two hours, 1-dimethylamino-2-nitroethylene is added and the reaction is slowly warmed to room temperature over the course of one hour. This affords the desired nitrovinyl pyrazole of formula (B) after work up and purification (Reaction scheme 1). Compounds of formula (A) are either known or can be prepared according to methods well known in the art.

Nitrovinyl pyrazole compounds of formula (B) can also be prepared by reacting the corresponding pyrazole aldehyde (x) and nitromethane together, with a suitable base, in a suitable solvent followed by dehydration step, as shown in Reaction scheme 1.1 below. Such methods are reported in WO2016/100050 and WO2019/169153.

The nitrovinyl pyrazole compound of formula (B) is then reacted with a malonate, such as diethylmalonate, in a suitable solvent, such as toluene, under enantioselective nickel catalysis as described in J. Am. Chem. Soc. 2005, 127, 9958-9959, to afford the enantio-enriched malonate addition product that is the compound of formula (C) as shown in Reaction scheme 2.

In compounds of formulae (A), (B), and (C), as described herein, ring A is a pyrazole moiety carrying two substituents, wherein one of said substituents (R^(B2)) is borne by a ring nitrogen, and a second substituent (R^(B3)) is borne on a ring carbon atom. Clearly with such a configuration, A is carbon linked to the rest of the respective molecule.

When A is di-substituted and R^(B3) is borne on the ring carbon atom adjacent the substituted ring nitrogen atom said R^(B3) substituent may be defined as R^(B3SN). For the avoidance of doubt R^(B3SN) is a sub-definition of R^(B3) used purely to denote positional placement within the pyrazole moiety, and therefore R^(B3SN) is also selected from the group consisting of halogen, C₁-C₃fluoroalkyl, C₁-C₃haloalkoxy, C₁-C₃alkoxy, and C₁-C₃alkyl. Thus, when A is di-substituted, it may be represented by groups A¹, A², A³, A⁴, or A⁵, as shown below, wherein R^(B2), R^(B3) and R^(B3SN) are as defined above and the jagged line denotes the point of attachment to the rest of the relevant molecule.

Groups A¹ and A² are particularly preferred, with A² being the most preferred of the di-substituted pyrazoles.

Preferably R^(B2) is selected from the group consisting of methyl, ethyl, n-propyl, fluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl and trifluoroethyl. More preferably R^(B2) is selected from the group consisting of methyl, ethyl, n-propyl, trifluoromethyl and difluoroethyl. More preferably still, R^(B2) is selected from the group consisting of methyl, ethyl, and difluoroethyl.

Preferably R^(B3) (and thus also R^(B3SN)) is selected from chloro, fluoro, bromo, methyl, ethyl, diluoromethyl, trifluoromethyl C₁-C₃haloalkoxy, C₁-C₃alkoxy, or C₁-C₃alkyl.

As used herein, the term “halogen” or “halo” refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo), preferably fluorine, chlorine or bromine.

Each alkyl moiety either alone or as part of a larger group may be straight-chained or branched, and as used herein the term specifically also includes cyclopropyl. Typically, the alkyl is, for example, methyl, ethyl, n-propyl, cylcopropyl, and isopropyl.

Table 1 and 2 below provide specific examples of compounds of formulae (B) and (C) for use in the invention.

TABLE 1 Compounds of formula B according to the invention Cmpd. No. Name Structure B.001 (E)-N,N-dihydroxy-2-[1-methyl-5-(trifluoromethyl)pyrazol-3- yl]ethenamine

B.002 (E)-N,N-dihydroxy-2-[1-methyl-5-(trifluoromethyl)pyrazol-4- yl]ethenamine

B.003 (E)-2-(5-chloro-1-methyl-pyrazol-3-yl)-N,N-dihydroxy- ethenamine

B.004 (E)-2-(5-chloro-1-methyl-pyrazol-4-yl)-N,N-dihydroxy- ethenamine

B.005 (E)-2-(5-fluoro-1-methyl-pyrazol-3-yl)-N,N-dihydroxy- ethenamine

B.006 (E)-2-(5-fluoro-1-methyl-pyrazol-4-yl)-N,N-dihydroxy- ethenamine

TABLE 2 Compounds of formula C according to the invention Cmpd. No. Name Structure C.001 diethyl 2-[(1R)-2-(dihydroxyamino)-1-[1-methyl-5- (trifluoromethyl)pyrazol-3-yl]ethyl]propanedioate

C.002 diethyl 2-[(1S)-2-(dihydroxyamino)-1-[1-methyl-5- (trifluoromethyl)pyrazol-4-yl]ethyl]propanedioate

C.003 diethyl 2-[(1R)-1-(5-chloro-1-methyl-pyrazol-3-yl)-2- (dihydroxyamino)ethyl]propanedioate

C.004 diethyl 2-[(1S)-1-(5-chloro-1-methyl-pyrazol-4-yl)-2- (dihydroxyamino)ethyl]propanedioate

C.005 diethyl 2-[(1R)-2-(dihydroxyamino)-1-(5-fluoro-1- methyl-pyrazol-3-yl)ethyl]propanedioate

C.006 diethyl 2-[(1S)-2-(dihydroxyamino)-1-(5-fluoro-1- methyl-pyrazol-4-yl)ethyl]propanedioate

Compounds of formula (B) and (C) as described herein, may be used to synthesise pyrazolo-lactam-carboxylates of formula (D),

wherein ring A, R^(B2) and R^(B3) are as defined herein, and pyrazolo-lactam-carboxylic acid derivatives of formula (E),

also wherein ring A, R^(B2) and R^(B3) are as defined herein. These novel compounds form yet further aspects of the invention.

The reductive cyclisation of the compound of formula (C), using a suitable reducing agent, such as sodium borohydride, with a suitable catalyst, such as nickel chloride, in a suitable solvent, such as ethanol, affords a pyrazolo-lactam-carboxylate of formula (D) (Reaction scheme 3 below).

The compound of formula (D) may then be hydrolysed in an aqueous hydroxide/ethanol mixture to afford the appropriate pyrazolo-lactam-3-carboxylic acid derivative of formula (E), as shown in Reaction scheme 4.

Compounds of formula (D) and formula (E) are also valuable intermediates in the production of pyrazolo-lactam herbicides, in particular as they give rise to the preferred herbicidal enantiomer. Tables 3 and 4 below provide specific examples of compounds of formulae (D) and (E) for use in the invention.

TABLE 3 Compounds of formula (D) according to the invention Cmpd. No. Name Structure D.001 ethyl (3R,4R)-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]- 2-oxo-pyrrolidine-3-carboxylate

D.002 ethyl (3R,4S)-4-[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]-2- oxo-pyrrolidine-3-carboxylate

D.003 ethyl (3R,4R)-4-(5-chloro-1-methyl-pyrazol-3-yl)-2-oxo- pyrrolidine-3-carboxylate

D.004 ethyl (3R,4S)-4-(5-chloro-1-methyl-pyrazol-4-yl)-2-oxo- pyrrolidine-3-carboxylate

D.005 ethyl (3R)-4-(5-fluoro-1-methyl-pyrazol-3-yl)-2-oxo- pyrrolidine-3-carboxylate

D.006 ethyl (3R)-4-(5-fluoro-1-methyl-pyrazol-4-yl)-2-oxo- pyrrolidine-3-carboxylate

TABLE 4 Compounds of formula (E) according to the invention Cmpd. No. Name Structure E.001 (3R,4R)-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo- pyrrolidine-3-carboxylic acid

E.002 (3R,4S)-4-[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]-2-oxo- pyrrolidine-3-carboxylic acid

E.003 (3R,4S)-4-(5-chloro-1-methyl-pyrazol-4-yl)-2-oxo-pyrrolidine- 3-carboxylic acid

E.004 (3R,4S)-4-(5-chloro-1-methyl-pyrazol-4-yl)-2-oxo-pyrrolidine- 3-carboxylic acid

E.005 (3R,4R)-4-(5-fluoro-1-methyl-pyrazol-3-yl)-2-oxo-pyrrolidine- 3-carboxylic acid

E.006 (3R,4S)-4-(5-fluoro-1-methyl-pyrazol-4-yl)-2-oxo-pyrrolidine- 3-carboxylic acid

The process for the manufacture of novel pyrazolo-lactam herbicides of formula (G) from compounds of formula (E), is described below in general terms in Reaction schemes 5 and 6, and with respect to a specific herbicidal compounds in the Examples.

Compounds of formula (E) are methylated on the lactam nitrogen using excess base, such as potassium tertiary butoxide, with methyl iodide or alternative methylating reagents, in a suitable solvent, such as tetrahydrofuran (Reaction scheme 5 above).

The 3-carboxyl substituted N-methyl lactam of formula (F) is coupled with an aniline of formula R²—NH₂ (wherein R² is as defined infra) to afford a herbicidal pyrazolo-lactam carboxamide of formula (G), using standard amide coupling conditions, such as propanephosphonic acid anhydride in a suitable solvent, such as dichloromethane, with a suitable base (Reaction scheme 6).

For anilines of formula R²—NH₂ and herbicidal compounds of formula (G), R² substituents include hydrogen, C₁-C₆alkyl, —C_(r)alkoxyC_(s)alkyl, C₁-C₆haloalkyl, —C_(r)alkoxyC_(s)haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, and —(CR²¹R²²)_(t)R²⁰, wherein each R²⁰ is independently —C(O)OR²³, —OC(O)R²³, —C₃-C₆cycloalkyl, or an -aryl, -aryloxy, -heteroaryl, -heteroaryloxy or -heterocyclyl ring, wherein said ring is optionally substituted by 1 to 3 independent R²⁵; r is an integer of 1, 2, 3, 4, or 5, s is an integer of 1, 2, 3, 4, or 5, and the sum of r+s is less than or equal to 6; t is an integer of 0, 1, 2, 3, 4, 5 or 6, each R²¹ is independently hydrogen or C₁-C₂ alkyl; each R²² is independently hydrogen or C₁-C₂ alkyl; R²³ is hydrogen or C₁-C₄alkyl.

In certain embodiments, where R² is an aryl or heteroaryl ring optionally substituted by 1 to 3 R²⁵, and said aryl or heteroaryl ring is selected from the group consisting of a phenyl, pyridinyl, and a thienyl ring system, it may be represented by the following generic structure

wherein ring B is a phenyl, pyridinyl, or thienyl ring, p is an integer or 0, 1, 2, or 3, and the jagged line represents the point of attachment of the ring to the rest of the molecule, in this case via the amide nitrogen.

In certain embodiments R² is selected from the group consisting of R²-1, R²-2, R²-3, R²-4, R²-5, and R²-6, wherein p and the jagged line are as described previously, and each R²⁵ is independently halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, cyano, nitro, C₁-C₆alkylthio, C₁-C₆alkylsulphinyl, or C₁-C₆alkylsulphonyl

More preferably each R²⁵ is independently halogen, C₁-C₄ alkyl, C₁-C₃ haloalkyl, C₁-C₃alkoxy, or C₁-C₃haloalkoxy; even more preferably chloro, fluoro, bromo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, or C₁-C₂alkoxy; more preferably still fluoro, ethyl, trifluoromethyl, difluoroethyl, methoxy, difluoromethoxy, or trifluoromethoxy. As stated herein, the value of p is 1, 2 or 3. Preferably p is 0, 1, or 2 and each R²⁵ is borne by a ring carbon atom.

Anilines of formula R²—NH₂ are either known or can be prepared according to methods well known in the art.

Reaction schemes 1a, 2a, 3a, 4a, and 5a shown below exemplify the compounds and processes of the invention as described above for a preferred set of embodiments, wherein the pyrazole ring in the compound of formula (A) has the structure described as A2 supra. Unless otherwise stated, R^(B2), R^(B3), Hal, and ^(R2) are as defined hereinbefore.

Various aspects and embodiments of the present invention will now be illustrated in more detail by way of example. It will be appreciated that modification of detail may be made without departing from the scope of the invention.

For the avoidance of doubt, where a literary reference, patent application, or patent, is cited within the text of this application, the entire text of said citation is herein incorporated by reference.

EXAMPLES Example 1: Preparation of the herbicidal compound (3S,4R)—N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide

The Nickel catalyst used in step 3, which catalyses the asymmetric malonate addition to the nitro olefin, can be prepared as in J. Am. Chem. Soc. 2005, 127, 9958-9959.

Step 1 3-iodo-1-methyl-5-(trifluoromethyl)pyrazole

The compound 1-methyl-5-(trifluoromethyl)pyrazol-3-amine (5.00 g, 30.3 mmol) was stirred in 9M sulfuric acid (818 mmol, 91 mL) in a 500 mL beaker, using an overhead stirrer at 0° C. (ice bath) until a homogenous mixture resulted. Sodium nitrite (60.6 mmol, 4.18 g), in 10 mL of water, was then added dropwise over 5 minutes, resulting in a colourless solution and the reaction was stirred at 0° C. for a further 20 minutes. Potassium iodide (75.7 mmol, 12.6 g), in 20 mL of water, was added dropwise to the reaction and the mixture was then stirred for a further 4 hours. The reaction was quenched with saturated sodium thiosulfate until the mixture became clear. The mixture was then diluted with dichloromethane and the phases were separated. The aqueous was further extracted with dichloromethane and the combined organic extracts were washed with water, dried (MgSO4), filtered and concentrated under vacuum to afford a pale yellow oil. The crude product was purified by column chromatography (EtOAc/hexanes gradient elution) to afford 3-iodo-1-methyl-5-(trifluoromethyl)pyrazole as a colourless oil, 3.9 g, (47%). ¹H NMR (400 MHz, CDCl₃) δ=6.76 (s, 1H) 4.01 (d, J=0.61 Hz, 3H).

Step 2 1-Methyl-3-[(E)-2-nitrovinyl]-5-(trifluoromethyl)pyrazole

Isopropylmagnesium chloride-Lithium chloride in THE (23.55 mmol, 1.3 mol/L) was added dropwise to 3-iodo-1-methyl-5-(trifluoromethyl)pyrazole (5.0 g, 18.12 mmol) in THE (90 mL) at −20° C. and the mixture was stirred for 2 hours. 1-Dimethylamino-2-nitroethylene (27.17 mmol, 3.321 g) was added and the reaction was slowly warmed to RT over 1 hour. The reaction mixture was then carefully quenched with 2 M HCl, and extracted with ethyl acetate. The organic extracts were washed with brine, dried (MgSO4), filtered, concentrated and purified by chromatography (EtOAc/cyclohexane gradient elution) to afford 1-methyl-3-[(E)-2-nitrovinyl]-5-(trifluoromethyl)pyrazole (74.6%) as a yellow oil, 2.99 g (74.6%).

¹H NMR (400 MHz, CDCl₃) δ=7.89 (d, J=13.7 Hz, 1H), 7.63 (d, J=13.7 Hz, 1H), 6.88 (s, 1H), 4.05 (d, J=0.6 Hz, 3H).

Step 3 Diethyl 2-[(1S)-1-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-nitro-ethyl]propanedioate

To a solution of 1-methyl-3-[(E)-2-nitrovinyl]-5-(trifluoromethyl)pyrazole (0.650 g, 2.94 mmol) in toluene (19.5 mL) was added diethyl malonate (0.676 mL, 4.41 mmol) followed by Nickel(II)Bis[(1R,2R)—N1,N2-bis(phenylmethyl)-1,2-cyclohexanediamine-N1,N2]dibromide (0.0588 mmol, 0.0472 g), and the mixture was stirred at ambient temperature for 20 hours.

The reaction mixture was washed with water (2×10 mL) and the organic phase separated, concentrated and purified by chromatography (EtOAc/cyclohexane gradient elution) to afford diethyl 2-[(1S)-1-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-nitro-ethyl]propanedioate as pale yellow oil, 1.07 g (95%).

¹H NMR (400 MHz, CDCl₃) δ=6.53 (s, 1H), 5.01 (dd, 1H), 4.88 (dd, J=4.3, 13.9 Hz, 1H), 4.35 (ddd, J=4.4, 7.7, 9.0 Hz, 1H), 4.22 (q, 2H), 4.16 (q, J=7.1 Hz, 2H), 3.90 (s, 3H), 3.89 (d, 1H), 1.26 (t, 3H), 1.20 (t, J=7.2 Hz, 3H).

Step 4 Ethyl (3R,4R)-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylate

To a solution of diethyl 2-[(1R)-1-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-nitro-ethyl]propanedioate (1.07 g, 2.81 mmol) in ethanol (42.1 mL) cooled to 0-5° C. (ice bath) under nitrogen, was added dichloronickel hexahydrate (2.95 mmol, 0.700 g). Sodium borohydride (8.42 mmol, 0.325 g) was then added portionwise to the pale greenish-blue solution. After 30 minutes the cooling was removed and the reaction mixture allowed to warm to ambient temperature. After stirring for 5 hours, at ambient temperature, the reaction mixture was cooled to 5-10° C., in an ice-water bath, and slowly quenched with ammonium chloride solution, and the mixture stirred for a further 20 minutes. The mixture was then diluted with EtOAc (20 mL), and filtered through a bed of celite, washing through with portions of water and EtOAc. The collected two-phase mixture was concentrated to remove the bulk of solvent and the residue transferred to a separating funnel, diluted with EtOAc (20 mL) and the organic phase separated. The aqueous phase was further extracted with EtOAc (2×25 mL) and all organic extracts combined, passed through a phase separation concentrated and purified by chromatography (EtOAc/hexanes gradient elution) to afford a pale yellow oil, 0.61 g (77%) which crystallised on standing.

1H NMR (400 MHz, CDCl₃) δ=6.91 (br s, 1H), 6.47 (s, 1H), 4.28 (q, J=7.2 Hz, 2H), 4.14 (q, 1H), 3.94 (d, 3H), 3.80 (dt, J=1.0, 9.0 Hz, 1H), 3.63 (d, J=9.3 Hz, 1H), 3.52 (dd, J=8.2, 9.5 Hz, 1H), 1.32 (t, J=7.2 Hz, 3H).

Step 5 (3R,4R)-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylic acid

To a solution of ethyl (3R,4R)-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylate (0.61 g, 2.0 mmol) in ethanol (6.0 mL) and water (2.0 mL) at 0° C. (ice bath) was added 2M sodium hydroxide (3 mL, 6.0 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and then diluted with water (15 mL) and extracted with EtOAc (25 mL). The organic extracts were washed with water (10 mL), and the aqueous extracts combined and acidified to pH 2 with dilute HCl. The acidified aqueous extracts were then re-extracted with EtOAc (3×20 mL) and these organic extracts were run through a phase separation cartridge and concentrated affording a pale yellow oil, 0.54 g (quantitative) which crystallised on standing.

¹H NMR (400 MHz, CDCl3) δ=6.59 (s, 1H), 4.09 (q, 1H), 3.94 (s, 3H), 3.85-3.77 (m, 1H), 3.72 (d, J=10.0 Hz, 1H), 3.66-3.58 (m, 1H).

Step 6 (3R,4R)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylic acid

To a stirred solution of (3R,4R)-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylic acid (0.57 g, 2.1 mmol, 0.57 g) in tetrahydrofuran (16 mL), at room temperature, under a nitrogen atmosphere was added potassium tertiary butoxide (1.0M in THF) (4.5 mL, 4.5 mmol) giving a pale yellow fine suspension. To this suspension was added iodomethane (0.19 mL, 3.1 mmol), and stirring at room temp was continued for 20 h. The stirred reaction mixture was acidified to pH2 with dilute HCl and the mixture was diluted with water (10 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (15 mL), dried over magnesium sulfate, filtered and the filtrate concentrated giving a transparent amber gum, 0.63 g ((quantitative).

¹H NMR: (400 MHz, CDCl3) δ=6.68 (s, 1H), 3.97 (q, 1H), 3.94 (s, 3H), 3.76-3.68 (m, 3H), 2.99 (s, 3H).

Step 7 (3S,4R)—N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide

To a solution of (3R,4R)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylic acid (0.61 g, 2.1 mmol) in dichloromethane (15 mL) was added 2,3-difluoroaniline (0.21 mL, 2.1 mmol). Propylphosphonic anhydride (50 mass %) in ethyl acetate (2.3 g, 3.6 mmol, 2.1 mL) was then added, and the reaction mixture was then immersed in a room temp water bath. N,N-Diisopropylethylamine (1.1 mL, 6.3 mmol) was added drop-wise, and the reaction was stirred at room temperature for 2.5 hour. The reaction mixture was quenched by the addition of water (15 mL) and transferred to a phase sep cartridge. The aqueous was further extracted with DCM (2×10 mL) and the combined organic extracts were concentrated and purified by chromatography (EtOAc/hexanes gradient elution) to afford a pink oil. Trituration with iso-hexane afforded a pale pink solid 398 mg (47%).

1H NMR: (400 MHz, CDCl₃) δ=10.16 (br s, 1H), 8.08-8.01 (m, 1H), 7.02 (ddt, J=2.1, 5.9, 8.3 Hz, 1H), 6.93-6.84 (m, 1H), 6.69 (s, 1H), 4.09 (q, 1H), 3.94 (s, 3H), 3.78 (d, J=9.5 Hz, 1H), 3.76-3.65 (m, 2H), 2.98 (s, 3H).

Chiral HPLC analysis, by the methods stated above, confirmed an enantiomeric ratio of 97:3.

Example 2 Preparation of (3S,4S)—N-(2,3-Difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]-2-oxo-pyrrolidine-3-carboxamide

The herbicidal compound (3S,4S)—N-(2,3-Difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]-2-oxo-pyrrolidine-3-carboxamide was made in a directly analogous manner to that described above for (3S,4R)—N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide in Example 1 above. NMR data for the single enantiomer is as follows:

1HNMR (CDCl3) δ=10.05 (br s, 1H), 8.04-7.97 (m, 1H), 7.46 (s, 1H), 7.01 (ddt, J=2.1, 5.9, 8.3 Hz, 1H), 6.93-6.84 (m, 1H), 4.21 (q, J=8.8 Hz, 1H), 4.00 (s, 3H), 3.75 (t, J=9.5 Hz, 1H), 3.64 (d, J=9.4 Hz, 1H), 3.27 (dd, J=8.1, 9.9 Hz, 1H), 2.97 (s. 3H). 

1. A method, comprising: reacting a compound of formula (A):

wherein ring A is a di-substituted pyrazole, substituted on a ring nitrogen by R^(B2) and substituted on a ring carbon by R^(B3), wherein R^(B2) is C₁-C₃ alkyl or C₁-C₃fluoroalkyl and R^(B3) is halogen, C₁-C₃haloalkoxy, C₁-C₃alkoxy, C₁-C₃haloalkyl, or C₁-C₃alkyl; and Hal is iodo, bromo or chloro, with 1-dimethylamino-2-nitroethylene to form a compound of formula (B):


2. The method of claim 1, wherein the reacting further comprises isopropylmagnesium chloride-lithium chloride and a solvent.
 3. The method of claim 2, wherein the solvent is tetrahydrofuran.
 4. The method of claim 3, wherein the reacting is at −20° C.
 5. The method of claim 2, wherein the reacting is warmed to room temperature after adding 1-dimethylamino-2-nitroethylene.
 6. The method of claim 2, wherein the compound of formula (B) is selected from the group consisting of: (E)-N,N-dihydroxy-2-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]ethenamine; (E)-N,N-dihydroxy-2-[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]ethenamine; (E)-2-(5-chloro-1-methyl-pyrazol-3-yl)-N,N-dihydroxy-ethenamine; (E)-2-(5-chloro-1-methyl-pyrazol-4-yl)-N,N-dihydroxy-ethenamine; (E)-2-(5-fluoro-1-methyl-pyrazol-3-yl)-N,N-dihydroxy-ethenamine; and (E)-2-(5-fluoro-1-methyl-pyrazol-4-yl)-N,N-dihydroxy-ethenamine.
 7. The method of claim 1, wherein the compound of formula (B) ring A is A1, A2, A3, or A5,

where the jagged line denotes attachment to the nitrovinyl moiety, R^(B2) is C₁-C₃ alkyl or C₁-C₃fluoroalkyl, and R^(B3) and R^(B3SN) are halogen, C₁-C₃haloalkoxy, C₁-C₃alkoxy, C₁-C₃haloalkyl, or C₁-C₃alkyl; or ring A is A⁴

where the jagged line denotes attachment to the nitrovinyl moiety, R^(B2) is C₁-C₃ alkyl or C₁-C₃fluoroalkyl, and R^(B3) is fluoro, bromo, iodo, C₁-C₃haloalkoxy, C₁-C₃alkoxy, C₁-C₃haloalkyl, or C₁-C₃alkyl; or ring A is A⁴

where the jagged line denotes attachment to the nitrovinyl moiety, R^(B2) is ethyl, n-propyl, cyclopropyl, isopropyl, or C₁-C₃fluoroalkyl, and R^(B3) is halogen, C₁-C₃haloalkoxy, C₁-C₃alkoxy, C₁-C₃haloalkyl, or C₁-C₃alkyl.
 8. The method of claim 1, wherein the compound of formula (B) ring A is A1, A2, A3, A4 or A5,

wherein R^(B3SN) is an R^(B3) substituent located on a carbon atom immediately adjacent the nitrogen atom substituted with R^(B2), and the jagged line denotes attachment to the nitrovinyl moiety.
 9. The method of claim 8, wherein the compound of formula (B) ring A is A1, A2, A3, or A5.
 10. A method, comprising: reacting a compound of formula (A):

wherein ring A is a di-substituted pyrazole, substituted on a ring nitrogen by R^(B2) and substituted on a ring carbon by R^(B3), wherein R^(B2) is C₁-C₃ alkyl or C₁-C₃fluoroalkyl and R^(B3) is halogen, C₁-C₃haloalkoxy, C₁-C₃alkoxy, C₁-C₃haloalkyl, or C₁-C₃alkyl; with nitromethane to form a compound of formula (B):


11. The method of claim 10, wherein the reacting further comprises a base.
 12. The method of claim 11, wherein the reacting further comprises a solvent.
 13. The method of claim 12, wherein the reacting further comprises dehydrating with a dehydrating agent.
 14. The method of claim 10, wherein the compound of formula (B) is selected from the group consisting of: (E)-N,N-dihydroxy-2-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]ethenamine; (E)-N,N-dihydroxy-2-[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]ethenamine; (E)-2-(5-chloro-1-methyl-pyrazol-3-yl)-N,N-dihydroxy-ethenamine; (E)-2-(5-chloro-1-methyl-pyrazol-4-yl)-N,N-dihydroxy-ethenamine; (E)-2-(5-fluoro-1-methyl-pyrazol-3-yl)-N,N-dihydroxy-ethenamine; and (E)-2-(5-fluoro-1-methyl-pyrazol-4-yl)-N,N-dihydroxy-ethenamine.
 15. The method of claim 10, wherein the compound of formula (B) ring A is A1, A2, A3, or A5,

where the jagged line denotes attachment to the nitrovinyl moiety, R^(B2) is C₁-C₃ alkyl or C₁-C₃fluoroalkyl, and R^(B3) and R^(B3SN) are halogen, C₁-C₃haloalkoxy, C₁-C₃alkoxy, C₁-C₃haloalkyl, or C₁-C₃alkyl; or ring A is A⁴

where the jagged line denotes attachment to the nitrovinyl moiety, R^(B2) is C₁-C₃ alkyl or C₁-C₃fluoroalkyl, and R^(B3) is fluoro, bromo, iodo, C₁-C₃haloalkoxy, C₁-C₃alkoxy, C₁-C₃haloalkyl, or C₁-C₃alkyl; or ring A is A⁴

where the jagged line denotes attachment to the nitrovinyl moiety, R^(B2) is ethyl, n-propyl, cyclopropyl, isopropyl, or C₁-C₃fluoroalkyl, and R^(B3) is halogen, C₁-C₃haloalkoxy, C₁-C₃alkoxy, C₁-C₃haloalkyl, or C₁-C₃alkyl.
 16. The method of claim 10, wherein the compound of formula (B) ring A is A1, A2, A3, A4 or A5,

wherein R^(B3SN) is an R^(B3) substituent located on a carbon atom immediately adjacent the nitrogen atom substituted with R^(B2), and the jagged line denotes attachment to the nitrovinyl moiety.
 17. The method of claim 16, wherein the compound of formula (B) ring A is A1, A2, A3, or A5. 